WO2006011637A1

WO2006011637A1 - Film-coated tablet

Info

Publication number: WO2006011637A1
Application number: PCT/JP2005/014149
Authority: WO
Inventors: Takayuki Murakami; Keiichi Fujiwara; Teruaki Kuriyama
Original assignee: Dainippon Sumitomo Pharma Co., Ltd.
Priority date: 2004-07-28
Filing date: 2005-07-27
Publication date: 2006-02-02
Also published as: JPWO2006011637A1; TW200605920A; JP4874797B2; KR20070046117A; CN1993131B; HK1107258A1; CN1993131A; KR101045508B1

Abstract

A rapidly dissolving film-coated tablet which contains 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (hereinafter referred to as 'compound (A)') or a physiologically acceptable salt thereof and has excellent storage stability. The rapidly dissolving film-coated tablet comprises (a) an uncoated tablet containing the compound (A) or a physiologically acceptable salt thereof and (b) a coating layer formed on the surface of the uncoated tablet, the coating layer containing substantially no plasticizer or containing at least one plasticizer selected from the group consisting of compounds having one or more ester bonds (e.g., triacetin).

Description

Specification

Buoy / REM coating

Technical field

The present invention relates to a film-coated tablet containing 4-1-amino-5-chloro-2-ethoxy-1-N-[[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof. About.

Background art

(F) 1-Amino-5-chloro-2-ethoxy 1-N- [[4 1 (4-Fnoreo benzyl) 1 2-morpholyl] methyl] benzamide (hereinafter sometimes referred to as “mosapride”) It is a selective serotonin 4 receptor agonist and has a good gastrointestinal motility promoting action (US Pat. No. 4,870,074). Mosapride or its physiologically acceptable salt is also useful as a treatment for reflux esophagitis, post-gastrectomy syndrome, and other gastrointestinal symptoms.

As a solid preparation containing mosapride, Example 2 45 5 of U.S. Pat. No. 4,870,074 describes a film-uncoated tablet containing quenate mosapride. . The tablet is a solid preparation containing mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropylcellulose, light anhydrous caustic acid and magnesium stearate.

Censic acid mosapride << dihydrate has already been put into practical use for the purpose of improving gastrointestinal symptoms associated with chronic gastritis. Tablets containing 2.5 mg or 5 mg as mosapride (anhydride) citrate (1.72 mg or 3.4 4 mg as mosapride) are named under the trademark “Gasmotin” in Japan. It is commercially available. Commercially available tablets are in the form of film-coated tablets because mosapride is a bitter drug, and is further packaged with aluminum to prevent the formation and coloring of by-products under long-term storage. .

Disclosure of the invention

The subject of the present invention contains mosapride or a physiologically acceptable salt thereof. It is an object of the present invention to provide a fast-dissolving film-coated tablet with excellent storage stability without the need for protective packaging such as aluminum packaging. The present inventors have intensively studied to solve this problem, and promote the degradation of mosapride depending on the type of a specific plasticizer considered necessary for forming a coating layer in a film-coated tablet. Some have found that there is something that inhibits (or does not affect) the degradation of mosapride. Therefore, we first tried to produce a film-coated tablet using a film coating composition from which the plasticizer had been removed. Unexpectedly, it was possible to decompose mosapride for long-term storage or without aluminum packaging. Was found to be suppressed, and coloring to the preparation was suppressed, and the present invention was completed.

Furthermore, as a result of repeated researches, the present inventors have found that if a formulation is prepared using a film coating composition containing a specific formulation component that can suppress the degradation of mosapride or does not affect the degradation, the production will be hindered. The present invention has been completed by finding that the decomposition of mosapride is suppressed and the coloring of the preparation is suppressed even without long-term storage and without aluminum packaging. In other words, the present invention relates to 4-amino-5-chloro-2-ethoxy-1-N — [[4- (4′-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof. A fast-dissolving film-coated tablet comprising a film-coated tablet which is substantially free of a plasticizer or is covered with a coating layer containing a specific formulation component.

More specifically, the following inventions are provided.

Item 1: 4-monoamino-5-chloro-2-ethoxy-1-N — [[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide (hereinafter referred to as “Compound A”) or its physiologically acceptable A fast-dissolving film-coating tablet containing a salt,

(a) an uncoated tablet containing Compound A or a physiologically acceptable salt thereof and

(b) The surface of the uncoated tablet is substantially free of a plasticizer or is triaceti , Jetyl phthalate, Diptyl sebacate, Tryptyl catenate, Jetyl cepacate, Glycerin fatty acid ester, Acetylated monodaliselide, Acetyl triethyl thioate, Acetyl liptaylate, Monostearin, Sorbitan monolaurate, Coating layer containing at least one specific formulation component selected from the group consisting of dioctyl phthalate, butyl phthalinole butyl dalicolate and medium chain fatty acid triglycerides

A film-coated tablet having:

Item 2: The film coating tablet according to Item 1, having a coating layer substantially free of a plasticizer.

Item 3: Triacetin, Jetyl phthalate, Diptyl sepacate, Triptyl citrate, Jetyl sebacate, Glycerin fatty acid ester, Acetylated monoglyceride, Acetyl triethyl citrate, Acetyl tributyl citrate, Monostearin, Sorbitan monolaurate Item 2. The film-coated tablet according to Item 1, further comprising a coating layer containing at least one specific formulation component selected from the group consisting of dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acid triglycerides.

Item 4: Specific formulation ingredients are triacetin, decyl phthalate, dibutyl sepacate, tryptyl citrate, decyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl cetyl catenate, and acetyl catenate Item 4. The finalem-coated tablet according to Item 3, which is selected from the group consisting of tributyl.

Item 5: The film-coated tablet according to Item 3, wherein the specific formulation component is selected from the group consisting of triacetin, decyl phthalate, dibutyl sepacate and triptyl citrate.

Item 6: The film-coated tablet according to Item 3, wherein the specific formulation component is triacetin.

Item 7: The content of the specific formulation component is about 0.1 to about 30% by weight in the coating layer Item 4. The film-coated tablet according to Item 3.

Item 8: The film coating tablet according to any one of Items 1 to 7, wherein the physiologically acceptable salt of Compound A is a dihydrate of the citrate salt of Compound A.

Item 9: The content of Compound A or a physiologically acceptable salt thereof is about 0.5 to about 70% by weight in terms of Compound A in the uncoated tablet, according to any one of Items 1 to 8 The film-coated tablet as described.

Item 10: When the film-coated tablet is stored in a container at 40 ° C and 75% RH for 6 months, the ratio of the amount of compound A related substance produced is Item 10. The film-coated tablet according to any one of Items 1 to 9, wherein the area percentage measured by the method is about 1% or less.

Item 11: A commercial package containing the film-coated tablet according to Item 1 and a document relating to the film-coated tablet, wherein the film-coated tablet is used to promote gastrointestinal motility function, improve symptoms after gastrectomy, or gastroesophageal A commercial package containing a description that can or should be used in the prevention or treatment of reflux disease in the description on the package or in the package.

Since the film-coated tablet of the present invention has the above-mentioned characteristics, compound A or a physiologically acceptable salt thereof is difficult to be decomposed and stored in a stable state without applying protective packaging such as aluminum packaging. can do. Furthermore, when the film-coated tablet of the present invention is taken, no bitterness is felt.

Brief Description of Drawings

FIG. 1 is a graph showing the results of a contact test of a compound A-a (a racemate of Compound A) of the present invention with a citrate and various components.

FIG. 2 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.

FIG. 3 is a graph showing the results of the stability test of the preparations obtained in Example 1 and Comparative Example 1.

FIG. 4 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2. It is fu.

FIG. 5 is a graph showing the results of the stability test of the preparations obtained in Example 2 and Comparative Example 2.

BEST MODE FOR CARRYING OUT THE INVENTION

The first aspect of the present invention is a fast-dissolving film comprising a plain tablet containing compound A or a physiologically acceptable salt thereof, and a coating layer substantially free of a plasticizer on the surface of the plain tablet. It is a coated tablet. The film-coated tablet has the effect of suppressing the decomposition of the compound A, which is an active ingredient, and preventing coloration of the preparation even if it is stored for a long period of time without being subjected to protective packaging such as aluminum packaging. The

Film-coated Fi / REM coated tablets usually contain a plasticizer in the coating layer (coating layer), and the plasticizer has been considered not to react with the active ingredient. However, as a result of the inventors' research, certain plasticizers, specifically polyethylene glycol, poloxamer, polysorbate, polyoxyethylene hydrogenated castor oil, glycerin, etc., and compound A or its physiologically acceptable It was found that contact with the salt promotes the decomposition of Compound A. Specifically, as shown in the following Reference Examples, when a compound A or a physiologically acceptable salt in the present invention is brought into contact with the above components, a very large amount of decomposed substances (related substances) are produced. It has been found. On the other hand, it was also found that there is a plasticizer that suppresses the decomposition of Compound A.

Therefore, it was found that the decomposition of Compound A was suppressed even during long-term storage when coated with a coating layer substantially free of a plasticizer that should normally be contained in the coating layer.

In this embodiment, “substantially free of a plasticizer” means not only a plasticizer having an action of promoting the decomposition of the compound A when contacted with the compound A but also suppressing the decomposition of the compound A (or It means not containing any plasticizer (which has no effect). Here, as the plasticizer, poloxamer, polysorbate, propylene glycol , Polyethylene glycol, glycerin, polyoxyethylene hydrogenated castor oil, triacetin, cetyl phthalate, dibutyl sepacate, tryptyl decanoate, jetyl sepacate, glyceryl fatty acid ester, acetylated monoglyceride, acetytrimethyl quinate Examples include acetyl butyl citrate, monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl dalicolate, and medium chain fatty acid triglycerides.

According to a second aspect of the present invention, there is provided a rapid dissolution comprising an uncoated tablet containing Compound A or a physiologically acceptable salt thereof, and a coating layer containing at least one specific formulation component on the surface of the uncoated tablet. Film-coated tablets. The above-mentioned film-coated tablet is a compound A which is an active ingredient even if it is not subjected to protective packaging such as aluminum packaging even in long-term storage because the coating process proceeds smoothly by blending specific formulation ingredients in the coating layer. It has the effect of not promoting the degradation of or inhibiting the degradation and inhibiting the coloring of the preparation. Also, there will be no trouble in manufacturing.

Specific formulation ingredients

Examples of the “specific formulation component” in this embodiment include triacetin, dimethyl phthalate, diptyl cepacate, triptinole citrate, cetyl cepacate, glyceryl fatty acid ester, acetylated monodaricelide, acetiltyl citrate, and acetyl butyl triacetate. , Monostearin, sorbitan monolaurate, dioctyl phthalate, butyl phthalyl butyl dalicolate, and medium chain fatty acid triglycerides. These compounds are generally blended into the preparation as a plasticizer. In addition, some of these compounds are incorporated into the preparations as dispersants, brighteners, stabilizers, surfactants, and the like.

Therefore, at least one of the specific formulation ingredients, specifically triacetin, decyl phthalate, diptyl cepacate, tryptyl citrate, cetyl sepacate, glyceryl fatty acid ester, acetylated monodaliselide, cetyl triethyl catenate, Acetylliptyl taenoate, monostearin, sorbita It is preferable that at least one component selected from the group consisting of dimethyl monolaurate, dioctyl phthalate, butyl phthalyl butyl glycolate and medium chain fatty acid triglyceride is blended in the coating layer. Thereby, the decomposition of Compound A is further suppressed, the coating layer becomes stronger, and tablet sliding (including fluidity) is also possible. Preferred are triacetin, phthalate, dibutyl sebacate, dibutyl sebacate, tributyl taenoate, cetyl sebacate, glyceryl fatty acid ester, acetylated monoglyceride, acetiltyl ethyl citrate and cetyl citrate, more preferably Triacetin, decyl phthalate, dibutyl septate and triptyl citrate.

The content of these specific formulation components is preferably about 0.1 to about 30% by weight, preferably about 2 to about 25% by weight, and more preferably about 7 to about 20% by weight in the coating layer. . Hereinafter, features and components common to the first and second embodiments of the present invention will be described. The “fast dissolution” of the film-coated tablet according to the present invention is the dissolution test described in the 14th revised Japanese Pharmacopoeia (37 ° C, paddle method, 50 rpm Z min, solvent 90 O m 1 In water), the elution rate after 30 minutes is about 85% or more. The elution rate is preferably 90% or more, more preferably 95% or more.

Compound A or a physiologically acceptable salt thereof

Compound A according to the present invention, namely 4-amino-1-5-chloro-2-ethoxy-N — [[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide, has the following formula:

As a selective serotonin 4 receptor agonist, Has an action to promote gastrointestinal motility. Compound A according to the present invention may be a racemate or one of the optically active forms, but a racemate is preferred. Compound A may be a free form or a physiologically acceptable salt thereof. The salt is preferably an acid addition salt. For example, organic acid addition salts include formate, acetate, lactate, adipate, kenate, tartaric acid, fumarate, methanesulfonate, maleate, etc. Addition of inorganic acids Examples of the salt include hydrochloride, sulfate, nitrate, phosphate and the like. Of these, citrate is particularly preferable. Furthermore, Compound A or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. The hydrate of citrate is preferable, and citrate dihydrate is particularly preferable.

The above compound A or a physiologically acceptable salt thereof can be produced, for example, by the method described in US Pat. No. 4,887,074 or a method analogous thereto.

纖

“Uncoated tablet” may be Compound A or its physiologically acceptable salt alone. Generally, it is formed by blending other formulation ingredients. Any of these other formulation ingredients can be used as long as they are not inconvenient to be added and need to be added. For example, binders, excipients, fluidizing agents, disintegrating agents and the like can be mentioned as examples.

The content of Compound A or a physiologically acceptable salt thereof is about 0.01 to about 90 weight in uncoated tablet in terms of Compound A. /. Preferably from about 0.5 to about 70% by weight, more preferably from about 0.5 to about 50% by weight, and even more preferably from about 0.5 to about 30% by weight.

Binder

Specific examples of the binder include gum arabic, starch paste, hydroxypropenoresenorerose, hydroxypropinoremethinoresenorerose, polyvinylinorenoreconole, Examples include punoleran, gelatin, ethinorescenellose, methinorecellulose, canolemellose sodium, dextrin, and povidone. Preferable examples include hydroxypropinoresenorerose, hydroxypropinoremethinoresenellose, povidone and the like. The amount of the binder should be an amount that maintains the hardness of the tablet and does not hinder disintegration in the gastrointestinal tract, and is usually about 0.5 to about 10% by weight in the uncoated tablet, preferably About 1 to about 7% by weight.

Excipient

Specific examples of excipients include lactose, starch, mannitol, crystalline cellulose, sucrose, erythritol, trehalose, anhydrous calcium hydrogen phosphate, sulfated sulfate, and lactose, starch, mannitol, crystalline cellulose, etc. Is preferred. The amount is usually about 5 to about 97% by weight in the uncoated tablet, preferably about 10 to about 80% by weight.

Superplasticizer

Specific examples of the fluidizing agent include light anhydrous caustic acid, magnesium metasilicate aluminate, etc., and light anhydrous caustic acid is preferred. The amount thereof is usually about in plain tablet 0. 0 1 to about 1 0 wt ° / _0, preferably about 0. 1 about 5 wt%.

Disintegrant

Examples of the disintegrating agent include low-substituted hydroxypropylcellulose, carmellose strength, croscarmellose sodium, crospovidone and the like. Of these, low-substituted hydroxypropylcellulose has a hydroxypropoxyl group content of usually about 5 to about 16% by weight, preferably about 7 to about 16% by weight. More preferably, about 10 to about 16% by weight is used. The blending amount of the disintegrating agent is usually about 2 to about 30% by weight, preferably about 5 to about 25% by weight in the uncoated tablet.

In addition, formulation ingredients such as lubricants such as magnesium stearate, zinc stearate, calcium stearate and the like may be blended as necessary.

The uncoated tablet should be compression-molded according to conventional methods by combining the above formulation ingredients as appropriate. Can be manufactured. Among these ingredients, lactose and starch as excipients, hydroxypropylcellulose as binder, light anhydrous caustic acid as fluidizing agent, low substituted hydroxypropyl cellulose as a disintegrating agent, stearic acid as lubricant It is preferred to select magnesium.

Coating layer

In addition to the above specific formulation ingredients, examples of the ingredients contained in the coating layer include the following.

Film base

Film bases include: Hydroxypropyl methylcellulose (HPMC), Hydroxypropylcellulose (HPC), Cellulose derivatives such as methylcellulose (MC), Ethylcellulose (EC), Polybulol alcohol (PVA), Polybulolpyrrolidone Examples thereof include vinyl polymers such as (PVP) and acrylic polymers such as methacrylic acid copolymers. Preferably, HPMC can be exemplified. The concentration of the film base in the coating layer is about 5 to about 100% by weight, preferably about 30 to about 100% by weight, especially about 50 to about 98% by weight in the case of a coating layer not containing a plasticizer. % Is preferred. In the case of a coating layer containing a specific formulation component, about 5 to about 99.9% by weight, preferably about 30 to about 98% by weight, especially about 50 to about 93% by weight is preferable.

Ingredients that may be added to the coating layer other than the above film base and the above specific formulation ingredients include, for example, colorants such as titanium oxide and iron sesquioxide (content in the coating layer: about 0 1 to about 50 wt./ ₀ ), anti-sticking agent such as talc (content in coating layer: about 0.1 to about 50 wt%), brightening agent such as light anhydrous caustic anhydride (coating layer Content: about 0.1 to about 10 weight ° / ₀ ). Other formulation ingredients may be added as needed.

In the coating layer forming step, one or more film bases (or film bases and specific formulation ingredients) described above are selected, and this is added to an organic solvent such as water or ethanol, preferably Liquid composition prepared by dissolving or suspending in water Can be carried out by spraying on the uncoated tablet. In addition, the coating liquid may contain the colorant, the anti-sticking agent, or the brightening agent, if necessary.

The film-coated tablet of the present invention is stable even during long-term storage. Therefore, when the film-coated tablet of the present invention is stored in a container and stored in the container for 6 months under an opening condition of 40 ° C and 75% RH, the amount of related substances produced (total amount of related substances) ) Is measured by high performance liquid chromatography, the percentage of the total related mass in area percentage is about 1% or less. It is preferably about 0.6% or less. The amount of related substances (total related substances) is the total amount of decomposition products of compound A, intermediates during production, impurities during production, etc., which are measured under the high-performance liquid chromatographic method described later. This means the total amount that can be detected. The area percentage refers to the number expressed in ° / ₀ of the ratio of the total peak area of related substances to the total peak area obtained by the high-speed liquid kumatograph method described later.

The measurement conditions in the high performance liquid chromatographic method are as described in the examples. The film coating agent of the present invention is suitably used for promoting gastrointestinal motility function, improving symptoms after gastrectomy, or preventing or treating gastroesophageal reflux disease (G E R D).

Example

The present invention will be illustrated more specifically with reference to the following examples, but the present invention is not limited to these examples.

In the following Examples and the like, the racemate of Compound A is defined as Compound A—a, and the citrate dihydrate of Compound A—a is defined as Compound A—b. A product manufactured by Nippon Pharmaceutical Co., Ltd. was used (average particle diameter of about 7 m).

Polyethylene Daricol 1 5 0 0 is “Polyethylene Glycol 1 5 0 0” manufactured by Nacalai Testa Co., Ltd., Polyethylene Glycol 4 0 0 is “Macrogol 4 0 0” of Maruishi Pharmaceutical Co., Ltd., Polyethylene Glycol 6 00 0 is “Macro Goal 6 0 0 0” manufactured by Nippon Oil & Fats Co., Ltd., Polysorbate 8 0 is “Polyoxyethylene sorbitan monooleate” manufactured by Nacalai Tesque Co., Ltd., Poloxamer 1 88 is “Pull-mouth Nick PE 6800” manufactured by BAS F Japan Co., Ltd., Glycerin is manufactured by Wako Pure Chemical Industries, Ltd., and sorbitan monolaurate is manufactured by Nacala Tester Co., Ltd. Jetyl phthalate was manufactured by Wako Pure Chemical Industries. Monostearin was manufactured by Nacalai Testa Co., Ltd., and triacetin was manufactured by Organic Synthetic Chemical Industry Co., Ltd.

For lactose, “Pharma tose ^R 200mesh” manufactured by DMV was used. As the starch, “Corn Starch” manufactured by Nippon Food Processing Co., Ltd. was used. Light anhydrous Kei acid was used to "Ae ro _S i 1 (registered trademark) 200" manufactured by Nippon Aerojiru CO., LTD. As the hydroxypropyl cellulose, “Nisso HPC L” manufactured by Nippon Soda Co., Ltd. was used. L-HP C (LH-1 l) j manufactured by Shin-Etsu Chemical Co., Ltd. was used as the low-substituted hydroxypropyl cellulose. As the magnesium stearate, plant-derived “magnesium stearate” manufactured by Taihei Chemical Industry Co., Ltd. was used. As the hydroxypropyl methylcellulose, “TC-1 5RW” manufactured by Shin-Etsu Chemical Co., Ltd. was used. Titanium oxide was “Titanium oxide” manufactured by Ishihara Sangyo Co., Ltd. The talc used was made by 3 Talc Co., Ltd.

Reference example

Compound A—b and various ingredients (polyethylene glycol 6000, polyethylene glycolol 1500, polyethylene glycolol 400, polysonolate 80, poloxamer 188, glycerin, sorbitan monolaurate, dimethyl phthalate, monostearin, triacetin) A change test was performed. That is, Compound A-b and various components were mixed in a glass container at a weight ratio of 1: 1, and a storage test was conducted at 60 ° C for 1 month after sealing. If it did not dissolve during compounding, it was in suspension or contact. As a comparative example, compound A—b was placed in a glass container, and after sealing, a storage test was also conducted at 60 ° C. for 1 month. After 1 month, the amount of related substances produced (total amount of related substances) was measured. The amount of related substances produced was measured by high performance liquid chromatography (area percentage). The total amount of related substances is It means the total amount of decomposition products, intermediates during production, impurities during production, etc. of compound Aa. The sample was prepared by adding water: methanol at a ratio of 1: 9 to the glass container and shaking for 20 minutes, followed by centrifugation to obtain a supernatant. The column used was D everosil ODS-7 (Nomura Chemical), and the mobile phase was a sodium citrate buffer (pH 3.4) nomethanol noacetonitrile mixture (24: 9: 7). The measurement wavelength was 274 nm.

The area percentage was determined by the following formula: (total peak area of related substances / total peak area) × 100.

The results are shown in Figure 1. Compound A—b was mixed with poloxamer 188, polyethylene glycols, polysorbate 80, or glycerin to produce an analog that was found to promote degradation. On the other hand, mixing compound A-b with sorbitan monolaurate, jetyl phthalate, monostearin or triacetin was found to be less decomposed than compound A-b alone or more than stored alone. did.

Example 1 Production of film-coated tablets

(1) Manufacture of uncoated tablets

Table 1: Ingredients of Hui ^^-coated tablets

Amount per tablet Compound A— b 5.29 mg

Lactose 61.6b mg

Starch 32.5 mg

Low substituted hydroxypropylcellulose 26.0 mg

Hydroxypropinoresenololose 2.6 mg

Magnesium stearate 1.3 mg

Light anhydrous caeic anhydride 0.65 mg

Uncoated tablet 130. mg According to the formulation shown in Table 1, uncoated tablets containing 3.43 mg of Compound Aa per tablet were produced. (1 3 Omg per tablet, round tablet, diameter 7. Omm).

(2) Formation of coating layer

Table 2: Coating components of film-coated tablets

Titanium oxide, talc, and light anhydrous caustic acid are added to and suspended in purified water, and then a 10% by weight hydroxypropylmethylcellulose aqueous solution prepared in advance is added and dispersed, and sieved with a sieve (No. 80). A coating solution was prepared.

Put 400 g (about 3100 tablets) of the uncoated tablets obtained in (1) above into a high coater (HC-LAB0 type, Freund Sangyo), spray the coating solution and dry the coating amount per tablet. 5. Coated to 0 Omg. After coating, the film was dried in a high coater to obtain the target film-coated tablet. Comparative Example 1

Example 1 Film-coated tablets in which the uncoated tablets obtained in (1) were coated with the coating described in Table 3 per tablet were produced as follows. Table 3: Coating components of film-coated tablets

After adding polyethylene glycol 6000, titanium oxide, talc and light anhydrous caustic acid to the purified water and suspending it, add 10% by weight aqueous solution of hydroxypropylpyrumethylcellulose prepared in advance and dispersing it. 80) to prepare a coating solution.

400 _{g of} uncoated tablets obtained in Example 1 (1) (about 3100 tablets) are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 1 tablet. Coated to 5.0 Omg per unit. After coating, drying was performed in a high coater.

Test Example 1 Stability test

The tablets obtained in Example 1 and Comparative Example 1 are (1) stored for 6 months at 40 ° C 75% RH in a glass bottle cap, or (2) stored for 6 months at 40 ° C 75% RH in a glass bottle opener. The amount of related substances produced (total amount of related substances) and hue changes were examined at regular intervals. The amount of related substances produced was determined by adding 1 ml of water and 9 ml of methanol to 2 tablets and preparing a sample according to the method described in the reference example. The high-speed liquid kumatograph method described in the reference example (area percentage) The hue change was determined visually. The results are shown in Figure 2 (glass bottle cap), Figure 3 (glass bottle cap), Table 4 (glass bottle cap) and Table 5 (glass bottle cap). Table 4: Hue change of glass bottle seals

Table 5: Hue change of glass bottle opener

As a result, even when the film-coated tablet of the present invention was stored for 6 months, the amount of related substances produced (total amount of related substances) was below the reference value (1%) under both open and closed conditions. It was. In addition, no change in hue was observed, which was stable.

As shown by the above results, the film-coated tablet of the present invention was excellent in stability under the conditions of 40 ° C. and 75% RH. Therefore, the film-coated tablet of the present invention can be stored in a certain amount without being individually packaged (for example, PTP packaging), so-called para-packaging is also possible. Therefore, the film-coated tablet of the present invention can be prescribed to patients in a simple packaged form (for example, wrapping with dalassin paper, medicine wrapping paper, etc.) or in a wand package packaged together at the time of taking. .

Test example 2 bitterness masking test

The bitterness masking test of the tablet obtained in Example 1 was conducted. That is, it was tested by three panelists whether or not there was an unpleasant taste shielding effect as compared with Compound A-b. As a result, the tablets of the example clearly have a shielding effect and the unpleasant taste I couldn't feel it at all.

Example 2 Film-coated tablets

According to the formulation shown in Table 6, uncoated tablets containing 1.72 mg of Compound A—a per tablet were manufactured (80 mg per tablet, round tablet, diameter 6.5 mm), and the coating solution consisting of the composition shown in Table 7 Thus, coating was carried out in the same manner as in Example 1 to produce the desired film-coated tablet.

Table 6: Uncoated tablets of film-coated tablets

Table 7: Coating components of film-coated tablets

Quantity per tablet Hydroxip pinole methinorescenellose

2.58 mg

Titanium oxide 0.30 mg

Talc 0.09 mg

Light anhydrous carboxylic acid 0.03 mg

Purified water 27. Omg

Coating solution 30mg

Coating amount 3 mg Comparative Example 2

The uncoated tablets obtained in Example 2 were coated with the composition shown in Table 8 per tablet to produce film-coated tablets.

Table 8: Coating components of film-coated tablets

After adding polyethylene glycol 6000, titanium oxide, talc, and light anhydrous caustic anhydride to purified water and suspending it, add a 10% by weight aqueous solution of hydroxypropylpyrumethylcellulose prepared in advance and disperse. And a coating solution was prepared.

400 g (about 5,000 tablets) of the uncoated tablets obtained in Example 2 are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 3.0 Omg per tablet. It was coated to become. After coating, drying was performed in a high coater.

Test Example 3 Stability test

(1) Store the tablets obtained in Example 2 and Comparative Example 2 at 40 ° C 75% RH for 6 months in a glass bottle cap, or (2) 6 bottles at 40 ° C 75% RH in a glass bottle opener Stored for a month and examined the amount of related substances produced (total amount of related substances) and hue changes at regular intervals. The amount of related substances produced was measured in the same manner as in Test Example 1, and the hue change was judged visually.

The results are shown in Fig. 4 (glass bottle cap), Fig. 5 (glass bottle cap), Table 9 (glass bottle cap) and Table 10 (glass bottle cap).

As a result, the film-coated tablets of the present invention have a reference value (1) for the amount of related substances produced (total amount of related substances), even after 6 months of storage, regardless of the conditions of opening and sealing. %) Or less. Moreover, the hue change was not recognized and it was stable. Table 9: Hue change of glass bottle seals

Table 10 0: Hue change of glass bottle opener

Example 3

Film-coated tablets, in which the uncoated tablets obtained in Example 1 (1) were coated with the coating described in Table 11 per tablet, were produced as follows. Table 11 1: Coating components of film-coated tablets

In purified water, Toriasechin, titanium oxide, was suspended adding talc Contact Yopi light anhydrous Kei acid was dispersed by adding 1 0 weight ^_0/0 hydroxypropylmethylcellulose cellulose solution prepared in advance was, screened (No. 80) and sieved to prepare a coating solution.

400 g of uncoated tablets obtained in Example 1 (1) (approximately 3100 tablets) are put into a high coater (HC-LAB0 type, Freund Sangyo), and the coating amount after drying by spraying the coating solution is 1 tablet. Coated to 5.0 O mg per unit. After coating, drying was performed in a high coater.

Test Example 4 Stability test

The tablets obtained in Example 3 were (1) stored for 1 month at 40 ° C and 75% RH by opening the glass bottle. The amount of related substances generated (total related substances) was The measurement was performed in the same manner. As a result, both tablets were stable.

Test Example 5 Dissolution test

Using the tablet of Example 1, the dissolution test was performed according to the dissolution test described in the 14th revised Japanese Pharmacopoeia (37 ° C, paddle method, 50 rpm, solvent 90 0 m 1 water). . So As a result, the elution rate after 30 minutes was 98.5%.

Industrial applicability

According to the film-coated tablet of the present invention, compound A or a physiologically acceptable salt thereof is hardly decomposed and can be stored in a stable state without carrying out protective packaging such as aluminum packaging. In addition, it will not interfere with production. Furthermore, it does not have a bitter taste when taken. While some of the specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed in the following claims.

This application is based on Japanese Patent Application No. 2 0 4 — 2 2 0 8 6 4 (filing date: July 2 8, 2004) filed in Japan, the contents of which are included in this specification. It is to be done.

Claims

The scope of the claims

1.4-Amino-5-chloro-2-ethoxy-N — [[4- (4-Fluorobenzyl) _2-morpholinyl] methyl] benzamide (hereinafter “Compound A”) or physiologically acceptable Fast-dissolving film-coating tablets containing the salt

(a) an uncoated tablet containing Compound A or a physiologically acceptable salt thereof; and (b) the surface of the uncoated tablet is substantially free of a plasticizer, or is triacetin, jetyl phthalate, sepasin Diptyl acid, Tryptyl citrate, Sephic acid cetyl acid, Glycerin fatty acid ester, Acetylated monodaliselide, Acetyl cetyl catenate, Acetino tryptyl citrate, Monostearin, Sorbitan monolaurate, Phtha / Reic acid Coating layer containing at least one specific formulation component selected from the group consisting of dioctinole, petit / refhtalyl ptyldalicolate and medium chain fatty acid triglycerides

A film-coated tablet having:

2. The film coating tablet according to claim 1, which has a coating layer substantially free from a plasticizer.

3. Triacetin, Jetyl phthalate, Dibutyl sepacate, Tryptyl catenate, Jetyl sebacate, Glycerin fatty acid ester, Acetylated monoglyceride, Acetyl triethyl catenate, Acetyl tributyl catenate, Monostearin, Sorbitan monolaurate 2. The finalem-coated tablet according to claim 1, further comprising a coating layer containing at least one specific formulation component selected from the group consisting of dioctyl phthalate, butyl phthalyl butyl glycolate, and medium-chain fatty acid triglycerides.

4. Specific formulation ingredients are Triacetin, Jetyl phthalate, Dibu sepacate 4. The film coating according to claim 3, wherein the film coating is selected from the group consisting of chill, tryptyl citrate, decyl sepacate, glyceryl fatty acid ester, acetylated monoglyceride, acetyl cetyl citrate and acetyl butyl decate. Tablets.

5. The film-coated tablet according to claim 3, wherein the specific formulation component is selected from the group consisting of triacetin, decyl phthalate, dibutyl sepacate and tryptyl citrate.

6. The film-coated tablet according to claim 3, wherein the specific formulation component is triacetin.

7. The film-coated tablet according to claim 3, wherein the content of the specific formulation component is about 0.1 to about 30% by weight in the coating layer.

8. The film-coated tablet according to any one of claims 1 to 7, wherein the physiologically acceptable salt of compound A is a hydrate of citrate of compound A.

9. The content of Compound A or a physiologically acceptable salt thereof is about 0.5 to about 70 wt ° / ₀ in terms of Compound A in an uncoated tablet, according to any one of Claims 1 to 8 The described Finorem coating key.

1. When the film-coated tablet is stored in a container at 40 ° C and 75% RH for 6 months, the ratio of the amount of compound A related substance produced is determined by the high performance liquid chromatographic method. The film-coated tablet according to any one of claims 1 to 9, having a measured area percentage of about 1% or less.

1 1. A commercial package containing the film-coated tablet according to claim 1 and a description relating to the film-coated tablet, wherein the film-coated tablet is used to promote gastrointestinal motility function, improve symptoms after gastrectomy, or A commercial package containing a description on or in the package that can or should be used for the prevention or treatment of gastroesophageal reflux disease.